The interleukin-2 receptor and related cytokine/cytokine receptor systems are being studied to understand critical components of the T cell immune response in normal and neoplastic cells. Following T-cell activation, IL-2 and IL-2 receptors are induced;the magnitude and duration of the T-cell immune response is controlled by the amount of IL-2 produced, the levels of receptors expressed, and the time course of these events. Expression of IL-2Ra is interestingly high in cells infected with HTLV-I, the cause of adult T cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). Three chains of the IL-2 receptor exist, IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb being significantly regulated at the level of transcription. gc is a shared chain also used by the receptors for IL-4, IL-7, IL-9, IL-15, and IL-21, and is the protein that is mutated in XSCID. We have focused primarily on the types of signals induced by some of these cytokines, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate cytokine/STAT target genes. Given our prior observations that STAT5A or STAT5B transgenic mice develop tumors, which was consistent with STAT5 being implicated in malignant transformation and elevated in a range of human tumors, this is an important area for both normal and pathological states. T helper cell differentiation is important in the regulation of host defense. Th1 differentiation is important for host defense to viruses and other intracelllular pathogens, Th2 differentiation is vital in allergic disorders and related to helminths, and Th17 differentiation is vital in a range of inflammatory disorders, including psoriasis and inflammatory bowel disease. We previously demonstrated that IL-2 plays an important role for Th2 differentiation and reported that IL-2 importantly regulates expression of the IL-4 receptor in a STAT5-dependent manner and critically controls priming of cells for Th2 differentiation. Moreover, using genome-wide Solexa-based ChIP-Seq analysis (a methodology combining chromatin immunoprecipitation with DNA sequencing), we had discovered that there is broad regulation of Th2 differentiation via STAT5 proteins, with both STAT5A and STAT5B being important. Moreover, IL-2-mediated IL-4Ra induction is a key step in priming cells for Th2 differentiation. Unexpectedly, whereas IL-4 can also upregulate IL-4Ra expression, T-cell receptor-mediated IL-4Ra induction is dependent on IL-2 rather than IL-4. These findings provided novel insights into the mechanism of priming for Th2 differentiation. An interesting observation was that whereas cytokine-mediate STAT protein activation in vitro is rapid but transient, we observed sustained STAT protein binding to target sites in vivo. Using the valuable ChIP-Seq data from this study, further related to Th differentiation, in a collaborative study with W.E. Paul's lab, we demonstrated that IL-1 family members (IL-1, IL-18, and IL-33) differentially cooperate with an inducer of STAT3, STAT5, or STAT6 to allow production of key cytokines and the propagation of an inflammatory state. We have continued studies of regulation of gc family cytokines and their receptors. Given the previous demonstration by the group that IL-21 regulates expression of BLIMP1, we have pursued the molecular basis for this observation, and a STAT3 site has been identified. Specifically, we analyzed the mechanism by which IL-21 regulates expression of the Prdm1 gene which encodes BLIMP1, a critical regulator of plasma cell differentiation. We found that it acts via a critical composite site that requires both STAT3 and IRF4. Moreover, using microarray and ChIP-Seq methodology, we demonstrate that these factors cooperate with each other in a more general way to globally regulate gene expression. We also implicated for the first time IRF4 in T follicular helper cell development. We have also continued more detailed basic studies of STAT proteins, including the importance of STAT tetramerization for gene regulation and to elucidate more about the role of STAT proteins in Adult T cell leukemia. Overall, the above findings enhance our understanding of mechanisms by which the gc family of cytokines control gene expression to regulate the immune response.